Differential regulation of plant innate immunity Project Summary The innate immune system detects pathogen-derived molecules to prevent infections via specialized immune receptors. The immune receptors include cell surface-resident pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) in mammals and receptor-like kinases (RLKs) in plants, and intracellular NOD-like receptors (NLRs), such as plant nucleotide-binding domain leucine-rich repeat proteins. Plant plasma membrane-localized RLKs function as PRRs that sense pathogen-associated molecular patterns (PAMPs) and collectively contribute to host immunity against a broad-spectrum of pathogens. Plant intracellular NLRs detect pathogen specific effector proteins that are translocated into host cells and trigger pathogen-specific immunity, often accompanied with programmed cell death. The genetic tractability of plants made it possible to identify many plant PRR and NLR immune receptors. However, how the signaling networks underlying PRR- and NLR- mediated immunity are interconnected remains largely unknown. The PI?s laboratory has developed a series of sensitive and high-throughput genetic screens to reveal the complex activation and signaling mechanisms in plant PRR- and NLR-mediated immunity. The screens point to an unexpected role of a group of RLKs with an extracellular malectin-like domain in plant immunity. The ample preliminary evidence supports a tantalizing hypothesis that specific malectin-like RLKs regulate two-tiered plant immunity and cell death by differential modulation of PRR and NLR immune receptor complexes. Specifically, this project seeks to elucidate: how malectin-like RLKs, LET1 and LET2, inversely regulate PRR and NLR complex formation and activation; how LET1/2 are modulated by glycosylphosphatidylinositol (GPI)-anchored LLG1 as an adaptor and secreted peptide RALF9 as a ligand; and how NLR protein SUMM2 stability is inversely regulated by two distinct E3 ubiquitin ligases. By elucidating cell surface-resident malectin-like RLK module as a molecular link of PRR and NLR immune receptors, the project has the potential to change the dogma of the interconnection of PRR and NLR- mediated immunity, which was previously thought to function independently at the receptor level and only converge in downstream signaling events. Plant PRR- and NLR-mediated immunity is analogous to mammalian TLR- and NLR-mediated innate immunity respectively. Uniquely, the enriched genetic and genomic resources, including the collection of whole-genome knockout lines, as well as the well-established cellular and biochemical assays present Arabidopsis as a tractable model system to understand the host immune mechanism at the whole organismal and physiological level. Thus, the impacts of the project will reach beyond plant biology and provide complementary views to the general understanding of innate immune signaling.